Abstract
Cushing’s disease (CD) is an endocrine disorder originated by a corticotroph tumor. It is linked with high mortality and morbidity due to chronic hypercortisolism. Treatment goals are to control cortisol excess and achieve long-term remission, therefore, reducing both complications and patient’s mortality. First-line of treatment for CD is pituitary’s surgery. However, 30% of patients who undergo surgery experience recurrence in long-term follow-up. Persistent or recurrent CD demands second-line treatments, such as pituitary radiotherapy, adrenal surgery, and/or pharmacological therapy. The latter plays a key role in cortisol excess control. Its targets are inhibition of adrenocorticotropic hormone (ACTH) production, inhibition of adrenal steroidogenesis, or antagonism of cortisol action at its peripheral receptor. Retinoic acid (RA) is a metabolic product of vitamin A (retinol) and has been studied for its antiproliferative effects on corticotroph tumor cells. It has been shown that this drug regulates the expression of pro-opiomelanocortin (POMC), ACTH secretion, and tumor growth in corticotroph tumor mouse cell lines and in the nude mice experimental model, via inhibition of POMC transcription. It has been shown to result in tumor reduction, normalization of cortisol levels and clinical improvement in dogs treated with RA for 6 months. The orphan nuclear receptor COUP-TFI is expressed in normal corticotroph cells, but not in corticotroph tumoral cells, and inhibits RA pathways. A first clinical human study demonstrated clinical and biochemical effectiveness in 5/7 patients treated with RA for a period of up to 12 months. In a recent second clinical trial, 25% of 16 patients achieved eucortisolemia, and all achieved a cortisol reduction after 6- to 12-month treatment. The goal of this review is to discuss in the context of the available and future pharmacological treatments of CD, RA mechanisms of action on corticotroph tumor cells, and future perspectives, focusing on potential clinical implementation.
Highlights
Cushing’s disease (CD) is a severe endocrine disorder associated with increased morbidity and mortality, caused by an adrenocorticotropic hormone (ACTH) secreting pituitary adenoma [1]
This study suggests that pasireotide is an effective drug for the long-term treatment of patients with CD, especially when surgery fails or is contraindicated [13]
glucocorticoid receptor (GR) Blockade Glucocorticoid receptor blockade can be used in selected patients, but these drugs are associated with pharmacological interactions and adverse events related to their mechanism of action such as arthralgia, nausea, headache, peripheral edema, decreased blood potassium, endometrial thickening, and require frequent monitoring
Summary
Cushing’s disease (CD) is a severe endocrine disorder associated with increased morbidity and mortality, caused by an adrenocorticotropic hormone (ACTH) secreting pituitary adenoma [1] It is the most common form of endogenous Cushing’s syndrome (CS) [2], and it is the consequence of excessive secretion of cortisol from the adrenal glands. It was approved in 2012 in US and Europe for the treatment of adult CD patients who did not achieve remission after surgery or when it has been contraindicated [7, 28, 32] This drug has been shown to suppress both ACTH secretion and cell proliferation [11]. In the first prospective phase III trial of monthly intramuscular long-acting release pasireotide (LAR), pasireotide normalized mean urinary free cortisol (UFC) in about 40% of 150 patients with CD at month 7 and showed a similar safety profile than twice-daily subcutaneous pasireotide [14]. Long term: 30% of 30 patients (mean dose 2.1 mg/week) and short term: 30–40% of 37 patients (mean dose 3.5 mg/week) normalized UFC
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